Recent research has yielded new therapeutic targets, consequently bolstering our comprehension of multiple cell death pathways, and motivating the development of innovative combinatorial therapies. Kartogenin While these approaches effectively reduce the therapeutic threshold, the potential for subsequent resistance remains a significant concern. Future therapies for PDAC resistance, safe from undue health risks and effectively designed, have the potential for foundation in discoveries applicable as a single approach or in a combinatorial manner. We investigate the factors contributing to PDAC chemoresistance in this chapter, and explore countermeasures targeting various pathways and cellular functions involved in the development and sustenance of chemoresistance.

Pancreatic ductal adenocarcinoma (PDAC), the most frequent pancreatic neoplasm (accounting for 90% of cases), is among the deadliest cancers of all malignancies. Aberrant oncogenic signaling, harbored by PDAC, potentially originates from diverse genetic and epigenetic modifications, including driver gene mutations (KRAS, CDKN2A, p53), regulatory gene amplifications (MYC, IGF2BP2, ROIK3), and disruptions in chromatin-modifying proteins (HDAC, WDR5), among other factors. PanIN (Pancreatic Intraepithelial Neoplasia) formation, a critical event, often stems from the presence of an activating KRAS mutation. Signaling pathways are diversified by mutated KRAS, affecting downstream targets such as MYC, playing a pivotal part in the progression of cancer. From the perspective of key oncogenic signaling pathways, this review delves into recent studies illuminating the origins of PDAC. We demonstrate how MYC, with the assistance of KRAS, both directly and indirectly modifies epigenetic reprogramming and the development of metastasis. Lastly, we summarize the emerging findings from single-cell genomic research, highlighting the variability in pancreatic ductal adenocarcinoma (PDAC) and its tumor microenvironment. This summary unveils potential molecular pathways for future PDAC treatment development.

The clinical course of pancreatic ductal adenocarcinoma (PDAC) is often characterized by a diagnosis at an advanced or metastatic stage, making it a challenging disease to manage. The United States anticipates a substantial increase in new cases (62,210) and deaths (49,830) by the close of this year, 90% of which are anticipated to be of the PDAC subtype. Though cancer therapy has advanced, the challenge of tumor diversity in pancreatic ductal adenocarcinoma (PDAC) persists, encompassing differences between patients and variations within the primary and secondary tumors of the same patient. Biosynthetic bacterial 6-phytase The PDAC subtypes are described in this review using the genomic, transcriptional, epigenetic, and metabolic signatures present in patients and across individual tumors. Recent investigations into PDAC biology reveal that heterogeneity within PDAC cells is a primary driver of disease progression, particularly under stress conditions like hypoxia and nutrient deprivation, leading to metabolic reprogramming. We thus aim to improve our understanding of the underlying mechanisms that impede the crosstalk between extracellular matrix constituents and tumor cells, which fundamentally shape the mechanics of tumor growth and metastasis. Pancreatic ductal adenocarcinoma (PDAC) cells are influenced by the intricate relationship they have with the different cell types within the tumor microenvironment, determining their tendency towards growth or regression and highlighting possibilities for targeted therapies. Finally, we draw attention to the dynamic, reciprocal effects of stromal and immune cells on immune surveillance or evasion, which are fundamental to the complicated process of tumorigenesis. The review, in its entirety, consolidates current knowledge on PDAC treatments, focusing on the diverse characteristics of tumor heterogeneity at multiple levels, thereby impacting disease progression and treatment resistance under stress.

Minority patients with pancreatic cancer, often underrepresented, experience varied access to cancer treatments, including clinical trials. To ameliorate outcomes for pancreatic cancer patients, the successful completion and conduct of clinical trials is vital. Consequently, a crucial consideration lies in optimizing patient eligibility for both therapeutic and non-therapeutic clinical trials. To combat bias, a deep understanding of individual, clinician, and system-level hurdles to clinical trial recruitment, enrollment, and completion is necessary for both clinicians and the health system. Improving enrollment of underrepresented minorities, socioeconomically disadvantaged individuals, and underserved communities in cancer clinical trials is critical for improving the generalizability of results and advancing health equity.

Among oncogenes implicated in human pancreatic cancer, KRAS, a significant member of the RAS family, is found to be mutated in ninety-five percent of cases. KRAS mutations induce its constant activation, triggering downstream signaling cascades like RAF/MEK/ERK and PI3K/AKT/mTOR, which in turn promote cellular proliferation and confer resistance to apoptosis in cancer cells. Researchers finally found a way to target the G12C mutation in KRAS with the first covalent inhibitor, proving the protein's previously held 'undruggable' status incorrect. G12C mutations, prevalent in non-small cell lung cancer, appear far less common in pancreatic cancer. In contrast, pancreatic cancer may exhibit further KRAS mutations like G12D and G12V. Whereas inhibitors specifically targeting the G12D mutation, exemplified by MRTX1133, have been recently developed, there is a notable absence of similar inhibitors for other mutations. Combinatorial immunotherapy Sadly, the ability of KRAS inhibitor monotherapy to be effective is undermined by the development of resistance. Hence, numerous combination therapies were investigated, with some achieving promising efficacy, for example, by combining receptor tyrosine kinase, SHP2, or SOS1 inhibitors. Recently, we have demonstrated a synergistic inhibition of G12C-mutated pancreatic cancer cell growth in both in vitro and in vivo models, achieved through the combination of sotorasib and DT2216, a selective BCL-XL degrader. KRAS-targeted therapies' adverse effect on cell cycle progression, particularly cellular senescence, can contribute to treatment resistance. However, this resistance can be overcome by combining these therapies with DT2216, which further promotes apoptosis. Combinatorial approaches, structurally similar to those used elsewhere, could have positive effects on G12D inhibitors in pancreatic cancer. This chapter will scrutinize KRAS biochemistry, its signaling pathways, the range of KRAS mutations, novel KRAS-targeted therapies under development, and combined treatment approaches. Ultimately, we delve into the obstacles to KRAS-based treatments, focusing on pancreatic cancer, and outline promising future directions.

Frequently diagnosed at an advanced stage, Pancreatic Ductal Adenocarcinoma (PDAC), or pancreatic cancer, is an aggressive malignancy that typically results in limited treatment options and produces modest clinical responses. By 2030, projections on cancer-related mortality in the United States anticipate pancreatic ductal adenocarcinoma to take the second position in frequency. Pancreatic ductal adenocarcinoma (PDAC) frequently exhibits drug resistance, leading to a substantial reduction in patients' overall survival rates. The almost uniform presence of oncogenic KRAS mutations in pancreatic ductal adenocarcinoma (PDAC) impacts over 90% of the patients. While effective medications aimed at specific KRAS mutations in pancreatic cancer exist, they are not currently used in clinical practice. In light of this, efforts persist in seeking alternative druggable targets or therapeutic strategies with the aim of enhancing outcomes for those afflicted with pancreatic ductal adenocarcinoma. KRAS mutations are commonly found in PDAC cases, and they activate the RAF-MEK-MAPK pathway, ultimately leading to pancreatic tumor development. The pancreatic cancer tumor microenvironment (TME) and chemotherapy resistance are profoundly influenced by the MAPK signaling cascade (MAP4KMAP3KMAP2KMAPK). Pancreatic cancer's immunosuppressive tumor microenvironment (TME) poses another obstacle to the effectiveness of chemotherapy and immunotherapy. T cell dysfunction and the progression of pancreatic tumors are significantly impacted by the presence and activity of immune checkpoint proteins, including CTLA-4, PD-1, PD-L1, and PD-L2. The activation of MAPKs, a molecular marker of KRAS mutations, and its consequences for the pancreatic cancer tumor microenvironment, resistance to chemotherapy, and the expression of immune checkpoint proteins are examined with a focus on their effect on clinical outcomes in PDAC patients. Consequently, grasping the intricate connection between MAPK pathways and the tumor microenvironment (TME) is fundamental to developing therapies that integrate immunotherapy and MAPK inhibitors, improving the efficacy of pancreatic cancer treatment.

The evolutionary conserved Notch signaling pathway, a critical signal transduction cascade in both embryonic and postnatal development, is, surprisingly, also implicated in tumorigenesis affecting multiple organs, including the pancreas, when functioning aberrantly. Due to late-stage diagnoses and a unique resistance to treatment, pancreatic ductal adenocarcinoma (PDAC), the most prevalent pancreatic malignancy, has a dismally low survival rate. In genetically engineered mouse models and human patients, preneoplastic lesions and PDACs display an upregulation of the Notch signaling pathway. The inhibition of Notch signaling, in turn, results in the suppression of tumor development and progression in mice as well as patient-derived xenograft tumor growth, underscoring the significant role of Notch in pancreatic ductal adenocarcinoma. Despite its significance, the role of the Notch signaling pathway in pancreatic ductal adenocarcinoma remains a matter of contention, as demonstrated by the varying functions of Notch receptors and the contrasting outcomes of inhibiting Notch signaling in murine models of PDAC that differ in their cellular origins or in their specific developmental stages.